1) Cryptococcosis in previously normal patients. Cryptococcus neoformans causes approximately 3000 cases of meningitis per year in non-HIV populations in the U.S. and the disease continues to have an attributable mortality of approximately 30% despite therapy. We have recruited approximately 100 patients with both meningoencephalitis and pulmonary disease. The protocol utilizes the latest in immunological and genetic methods and is divided in two parts: 1) to characterize and apply novel therapeutics to the acute phase of the disease to improve outcomes and 2) identify genetic and immunological risk factors involved in susceptibility to the disease. 1) We recently identified a new syndrome in cryptococcal infections in CM, a post-infectious inflammatory syndrome, (PIIRS), which results in a dysfunctional activated immune response within the brains of patients after microbiological control of the organism with standard therapies. Immunological profiling identified several biomarkers of PIIRS, such as sCD27, a measure of T-cell activation and sCD21, a marker of B-cell activation. Within the restricted confines of the skull, this excessive immune activity causes the brain to swell and become dysfunctional, resulting in coma and death. In collaboration with NINDS (B. Bielekova, O. Khan and A. Nath) and the neurosurgical service of the NIH clinical center (P. Chittiboina), we are utilizing corticosteroids and immune suppressants that have resulted in dramatic reductions in mortality for this disease. Presently, we have expanded this understanding of PIIRS to an under-recognized syndrome of CM-spinal arachnoiditis, which causes a paralyzing lower motor neuron syndrome in about 25% of patients with non-HIV-associated cryptococcal meningitis. We have also validated an additional CSF marker of neuroinflammation, sCD25, using our previous samples, that can be used to monitor patients with PIIRS in clinical practice. 2) Host susceptibility to cryptococcal disease in previously healthy individuals. a) Autoantibody to host cytokines: Previously, in collaboration with S. Browne of LCID, we had identified patients with C. gattii, a related form of Cryptococcus with an autoantibody to the macrophage stimulator granulocyte-monocyte stimulating factor, GM-CSF. We are presently studying the regulatory pathway of GM-CSF signaling and have found that autophagy plays a key role in this process, suggesting novel mechanisms for intervention. b) Genetic Defects: We have currently performed whole exome sequencing on 75 patients with CM disease and are currently pursuing several interesting leads including a CM patient with mutation in a soluble transporter who has a family history of early dementia and a set of distantly related patients with an unusual eosinophilic response to cryptococcal disease and defects in macrophage responses to activating cytokines. C) Idiopathic CD4 lymphopenia (ICL). Low numbers of a subset of T-cells, CD4 cells are typically associated with infections with opportunistic pathogens such as C. neoformans in other diseases such as HIV. However, many individuals have been identified with ICL that are healthy and never get infections. We have also identified two patients within a cohort of ICL that developed cryptococcal meningitis that have a second defect-- in one a mutation in NF-kappa B-essential modulator (NEMO), involved in T-cell recognition of immune molecules and a second, an autoantbody to GM-CSF. Since many patients with GMCSF autoantibody also do not develop cryptococcal meningitis, these patients may provide examples of how a genetic or autoimmune second hit may push an individual with ICL to become susceptible to CM and may also suggest why many patients with cryptococcal disease do not have a strong family history of the disease more typical of Mendelian diseases.